We use Density Functional methods to model the synthesis of acyl pyrrolidines from an oxazolidine starting material via the aza-Cope – Mannich (ACM) reaction. Specifically, we investigate the effect of a tosyl protecting group at the nitrogen position on reaction stereoselectivity by examining two oxazolidines that differ by a methyl substituent at the carbinol carbon position. In addition to delineating the reaction pathway for each of the possible diastereomers, we use the Eyring-Arrhenius equation to calculate the rate of conversion between minima and the expected ratio of products diastereomers. We find that activation energies for the initial oxazolidine-opening step are high and often rate-determining. After taking into account activation barriers for the ACM concerted step and for bond rotations that interconvert among stereoisomers, we find that both substrates should be selective for the same pyrrolidine diastereomer.

Kinetic analysis of the aza-Cope/Mannich reaction of substituted oxazolidines: Effect of an electron-withdrawing group

251st National Meeting (2016)

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